Verapamil disposition--effects of sulphinpyrazone and cimetidine

The effects of separate 7 day pretreatments with sulphinpyrazone (800 mg daily) and cimetidine (1 g daily) on the disposition of (+/-)-verapamil have been examined in eight healthy volunteers (four male, four female). Each subject received single oral (80 mg) and intravenous (0.15 mg/kg) doses of verapamil on different occasions before and after each pretreatment. Following sulphinpyrazone pretreatment, verapamil apparent oral plasma clearance (CLpo) increased from 4.27 to 13.77 l h-1 kg-1 (s.e. mean 0.51--ANOVA) (P less than 0.001); CL increased from 1.05 to 1.20 l h-1 kg-1 (s.e. mean 0.05) (P less than 0.05) and Fpo decreased from 27 to 10% administered dose (s.e. mean 2) (P less than 0.001). Vss and t1/2,z were unchanged. There was no sex difference for any dispositional parameter in the control phase, but the increase in CLpo following sulphinpyrazone pretreatment was more marked in males (4.04 to 17.33 l h-1 kg-1) than in females (4.49 to 10.21 l h-1 kg-1) (s.e. mean 0.72) (P less than 0.01). There was no significant change in any verapamil disposition parameter following cimetidine pretreatment. Verapamil unbound fraction in plasma was 0.157 (s.e. mean 0.001, n = 40). There was no alteration in verapamil plasma protein binding associated with increasing verapamil concentration (25-250 micrograms l-1) or addition of sulphinpyrazone (50-500 mg l-1) or cimetidine (0.5-5 mg l-1). The results suggest that sulphinpyrazone induces the metabolic clearance of (+/-)-verapamil with a sex difference in the response.(ABSTRACT TRUNCATED AT 250 WORDS)